The present invention relates to pharmaceutical preparations comprising substituted benzimidazole proton pump inhibiting agents.
Omeprazole is a substituted benzimidazole, 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl]sulfinyl]-1H-benzimidazole, that inhibits gastric acid secretion. Omeprazole belongs to a class of anti secretory compounds called proton pump inhibitors proton pump inhibiting agents (xe2x80x9cPPIsxe2x80x9d) that do not exhibit aniti-cholinergic or H2 histamine antagonist properties. Drags of this class suppress gastric acid secretion by the specific inhibition of the H+, K+-ATPase enzyme system (proton pump) at the secretory surface of the gastric parietal cell.
Typically, omeprazole, lansoprazole and other proton pump inhibitors are formulated in an enteric-coated solid dosage form (as either a delayed-release capsule or tablet) or as an intravenous solution (as a product for reconstitution), and are prescribed for short-term treatment of active duodenal ulcers, gastric ulcers, gastroesophageal reflux disease (GERD), severe erosive esophagitis, poorly responsive symptomatic gastroesophageal reflux disease, and pathological hypersecretory conditions such as Zollinger Ellison syndrome. These conditions are caused by an imbalance between acid and pepsin production, called aggressive factors, and mucous, bicarbonate, and prostaglandin production, called defensive factors. These above-listed conditions commonly arise in healthy or critically ill patients, and may be accompanied by significant upper gastrointestinal bleeding.
H2-antagonists, antacids, and sucralfate are commonly administered to minimize the pain and the complications related to these conditions. These drugs have certain disadvantages associated with their use. Some of these drugs are not completely effective in the treatment of the aforementioned conditions and/or produce adverse side effects, such as mental confision, constipation, diarrhea, and thrombocytopenia. H2-antagonists, such as ranitidine and cimetidine, are relatively costly modes of therapy, particularly in NPO patients, which frequently require the use of automated infusion pumps for continuous intravenous infusion of the drug.
Patients with significant physiologic stress are at risk for stress-related gastric mucosal damage and subsequent upper gastrointestinal bleeding (Marrone and Silen, Pathogenesis, Diagnosis and Treatment of Acute Gastric Mucosa Lesions, CLIN GASTROENTEROL 13:635-650 (1984)). Risk factors that have been clearly associated with the development of stress-related mucosal damage are mechanical ventilation, coagulopathy, extensive burns, head injury, and organ transplant (Zinner et al., The Prevention of Gastrointestinal Tract Bleeding in Patients in an Intensive Care Unit, SURG. GYNECOL. OBSTET., 153:214-220 (1981); Larson et al., Gastric Response to Severe Head Injury, AM. J. SURG. 147:97-105 (1984); Czaja et al., Acute Gastroduodenal Disease After Thermal Injury: An Endoscopic Evaluation of Incidence and Natural History, N ENGL. J. MED, 291:925-929 (1974); Skillman et al., Respiratory Failure, Hypotension, Sepsis and Jaundice: A Clinical Syndrome Associated with Lethal Hemorrhage From Acute Stress Ulceration, AM. J. SURG., 117:523-530 (1969); and Cook et al., Risk Factors for Gastrointestinal Bleeding in Critically Ill Patients, N. ENGL. J. MED., 330:377-381 (1994)). One or more of these factors are often found in critically ill, intensive care unit patients. A recent cohort study challenges other risk factors previously identified such as acid-base disorders, multiple trauma, significant hypertension, major surgery, multiple operative procedures, acute renal failure, sepsis, and coma (Cook et al., Risk Factors for Gastrointestinal Bleeding in Critically Ill Patients, N. ENGL. J. MED., 330:377-381 (1994)). Regardless of the risk type, stress-related mucosal damage results in significant morbidity and mortality. Clinically significant bleeding occurs in at least twenty percent of patients with one or more risk factors who are left untreated (Martin et al., Continuous Intravenous cimetidine Decreases Stress-related Upper Gastro-intestinal Hemorrhage Without Promoting Pneumonia, CRIT. CARE MED., 21:19-39 (1993)). Of those who bleed, approximately ten percent require surgery (usually gastrectomy) with a reported mortality of thirty percent to fifty percent (Czaja et al., Acute Gastroduodenal Disease After Thermal Injury: An Endoscopic Evaluation of Incidence and Natural History, N ENGL. J. MED, 291:925-929 (1974); Peura and Johnson, Cimetidine for Prevention and Treatment of Gastroduodenal Mucosal Lesions in Patients in an Intensive Care Unit, ANN INTERN MED., 103:173-177 (1985)). Those who do not need surgery often require multiple transfusions and prolonged hospitalization. Prevention of stress-related upper gastrointestinal bleeding is an important clinical goal.
Omeprazole (Prilosec((copyright)), lansoprazole (Prevacid(copyright)) and other proton pump inhibitors reduce gastric acid production by inhibiting H30 , K+-ATPase of the parietal cellxe2x80x94the final common pathway for gastric acid secretion (Fellenius et al., Substituted Benzimidazoles Inhibit Gastric Acid Secretion by Blocking H+, K+-ATPase, NATURE, 290:159-161 (1981); Wallmark et al, The Relationship Between Gastric Acid Secretion and Gastric H+, K+-ATPase Activity, J. BIOL.CHEM., 260:13681-13684 (1985); Fryklund et al., Function and Structure of Parietal Cells After H+, K+-ATPase Blockade, AM. J. PHYSIOL., 254 (3 PT 1); G399-407 (1988)).
Proton pump inhibitors contain a sulfinyl group in a bridge between substituted benzimidazole and pyridine rings, as illustrated below. 
At neutral pH, omeprazole, lansoprazole and other proton pump inhibitors are chemically stable, lipid-soluble, weak bases that are devoid of inhibitory activity. These neutral weak bases reach parietal cells from the blood and diffuse into the secretory canaliculi, where the drugs become protonated and thereby trapped. The protonated agent rearranges to form a sulfenic acid and a sulfenamide. The sulfenamide interacts covalently with sulfhydryl groups at critical sites in the extracellular (luminal) domain of the membrane-spanning H+, K+-ATPase (Hardman et al., Goodman and Gilman""s The Pharmacological Basis of Therapeutics, p. 907 (9th ed. 1996)). Omeprazole and lansoprazole, therefore, are prodrugs that must be activated to be effective. The specificity of the effects of proton pump inhibitors is also dependent upon: (a) the selective distribution of H+, K+-ATPase; (b) the requirement for acidic conditions to catalyze generation of the reactive inhibitor; and (c) the trapping of the protonated drug and the cationic sulfenamide within the acidic canaliculi and adjacent to the target enzyme. (Hardman et al., 1996).
Omeprazole and lansoprazole are available for oral administration as enteric-coated granules in gelatin capsules. Other proton pump inhibitors such as rabeprazole and pantoprazole are supplied as enteric-coated dosage forms. The enteric dosage forms of the prior art have been employed because they are acid labile; thus, it is important that these drugs not be exposed to low pH gastric acid prior to absorption. Although these drugs are stable at alkaline pH, they are destroyed rapidly as pH falls (e.g., by gastric acid). Therefore, if the micro-encapsulation or the enteric coating is disrupted (e.g., trituration to compound a liquid, or chewing the capsule), the dosage forms of the prior art will be exposed to degradation by the gastric acid in the stomach.
The absence of an intravenous or oral liquid dosage form in the United States has limited the testing and use of omeprazole, lansoprazole and rabeprazole in the critical care patient population. Barie et al., Therapeutic Use of Omeprazole for Refractory Stress-induced Gastric Mucosal Hemorrhage, CRIT. CARE MED., 20:899-901 (1992) have described the use of omeprazole enteric-coated pellets administered through a nasogastric tube to control gastrointestinal hemorrhage in a critical care patient with multi-organ failure. However, such pellets are not ideal as they can aggregate and occlude such tubes, and they are not suitable for patients who cannot swallow the pellets. AM J. HEALTH-SYST PHARM 56:2327-30 (1999).
Proton pump inhibitors such as omeprazole represent an advantageous alternative to the use of H2-antagonists, antacids, and sucralfate as a treatment for complications related to stress-related mucosal damage. However, in their current form (capsules containing enteric-coated granules or enteric-coated tablets), proton pump inhibitors can be difficult or impossible to administer to patients who are either unwilling or unable to swallow tablets or capsules, such as critically ill patients, children, the elderly, and patients suffering from dysphagia. Therefore, it would be desirable to formulate a proton pump inhibitor solution or suspension which can be enterally delivered to a patient thereby providing the benefits of the proton pump inhibitor without the drawbacks of the current enteric-coated solid dosage forms.
Omeprazole, the first proton pump inhibitor introduced into use, has been formulated in many different embodiments such as in a mixture of polyethylene glycols, adeps solidus and sodium lauryl sulfate in a soluble, basic amino acid to yield a formulation designed for administration in the rectum as taught by U.S. Pat. No. 5,219,870 to Kim.
U.S. Pat. No. 5,395,323 to Berglund (""323) discloses a device for mixing a pharmaceutical from a solid supply into a parenterally acceptable liquid form for parenteral administration to a patient. The ""323 patent teaches the use of an omeprazole tablet which is placed in the device and dissolved by normal saline, and infused parenterally into the patient. This device and method of parenteral infusion of omeprazole does not provide the omeprazole solution as an enteral product, nor is this omeprazole solution directly administered to the diseased or affected areas, namely the stomach and upper gastrointestinal tract, nor does this omeprazole formulation provide the immediate antacid effect of the present formulation.
U.S. Pat. No. 4,786,505 to Lovgren et al. discloses a pharmaceutical preparation containing omeprazole together with an alkaline reacting compound or an alkaline salt of omeprazole optionally together with an alkaline compound as a core material in a tablet formulation. The core is then enterically coated. The use of the alkaline material, which can be chosen from such substances as the sodium salt of carbonic acid, are used to form a xe2x80x9cmicro-pHxe2x80x9d around each omeprazole particle to protect the omeprazole which is highly sensitive to acid pH. The powder mixture is then formulated into enteric-coated small beads, pellets, tablets and may be loaded into capsules by conventional pharmaceutical procedures. This formulation of omeprazole does not teach a non-enteric-coated omeprazole dosage form which can be enterally administered to a patient who may be unable and/or unwilling to swallow capsules, tablets or pellets, nor does it teach a convenient form which can be used to make an omeprazole or other proton pump inhibitor solution or suspension.
Several buffered omeprazole oral solutions/suspensions have been disclosed. For example, Pilbrant et al., Development of an Oral Formulation of Omeprazole, SCAND. J. GASTROENT. 20(Suppl. 108): 113-120 (1985) teaches a suspension of micronized omeprazole, 60 mg, in 50 ml of water also containing 8 mmoles of sodium bicarbonate. The suspension was administered as follows: After fasting for at least 10 hours, patients were given a solution of 8 mmoles of sodium bicarbonate in 50 ml of water. Five minutes later the patients took the omeprazole suspension and rinsed it down with another 50 ml of sodium bicarbonate solution. Ten (10), 20 and 30 minutes later, a further 50 ml of sodium bicarbonate solution was administered.
Andersson et el., Pharmacokinetics of Various Single Intravenous and Oral Doses of Omeprazole, EUR J. CLIN. PHARMACOL. 39:195-197 (1990) discloses 10 mg, 40 mg, and 90 mg of oral omeprazole dissolved in PEG 400, sodium bicarbonate and water. The concentration of omeprazole cannot be determined, as volumes of diluent are not disclosed. Nevertheless, it is apparent from this reference that multiple doses of sodium bicarbonate were administered with and after the omeprazole suspension.
Andersson et al., Pharmacokinetics and Bioavailability of Omeprazole After Single and Repeated Oral Administration in Healthy Subjects, BR. J. CLIN. PHARMAC. 29:557-63 (1990) teaches the oral use of 20 mg of omeprazole, which was dissolved in 20 g of PEG 400 (sp. gravity=1.14) and diluted with 50 ml of water containing 8 mmoles of sodium bicarbonate. In order to protect the omeprazole from gastric acid, the buffered solution was given with 48 mmoles of sodium bicarbonate in 300 ml of water.
Regardh et al., The Pharmacokinetics of Omeprazole in Humansxe2x80x94A Study of Single Intravenous and Oral Doses, THER. DRUG MON. 12:163-72 (1990) discloses an oral dose of omeprazole at a concentration 0.4 mg/ml after the drug was dissolved in PEG 400, water and sodium bicarbonate (8 mmoles). A solution containing 16 mmoles of sodium bicarbonate in 100 ml of water was concomitantly given with the omeprazole solution. That dose was followed by a solution of 50 ml of 0.16 mol/L sodium bicarbonate that was used for rinsing the vessel. In both the IV and oral experiment, 50 ml of 0.16 mol/L sodium bicarbonate was administered 5 minutes before administration, and 10, 20 and 30 minutes post-dose.
Landahl et al., Pharmacokinetics Study of Omeprazole in Elderly Healthy Volunteers, CLIN. PHARMACOKINETICS 23 (6): 469-476 (1992) teaches the use of an oral dose of 40 mg of omeprazole dissolved in PEG 400, sodium bicarbonate and water. This reference does not disclose the final concentrations utilized. Again, this reference teaches the multiple administration of sodium bicarbonate (8 mmol/L and 16 mmol/L) after the omeprazole solution.
Andersson et al., Pharmacokinetics of [14C] Omeprazole in Patients with Liver Cirrhosis, CLIN. PHARMACOKINETICS 24(1): 71-78 (1993) discloses the oral administration of 40 mg of omeprazole, which was dissolved in PEG 400, water and sodium bicarbonate. This reference does not teach the final concentration of the omeprazole solution administered, although it emphasizes the need for pre, concomitant and post sodium bicarbonate dosing with a total of 48 mmoles to prevent acid degradation of the drug.
Nakagawa, et al., Lansoprazole: Phase I Study of lansoprazole (AG-1749) Anti-ulcer Agent, J. CLIN. THERAPEUTICS and MED.(1991) teaches the oral administration of 30 mg of lansoprazole suspended in 100 ml of sodium bicarbonate, which was administered to patients through a nasogastric tube.
All of the buffered omeprazole solutions described in these references were administered orally, and were given to healthy subjects who were able to ingest the oral dose. In all of these studies, omeprazole was suspended in a solution including sodium bicarbonate, as a pH buffer, in order to protect the acid sensitive omeprazole during administration. In all of these studies, repeated administration of sodium bicarbonate both prior to, during, and following omeprazole administration were required in order to prevent acid degradation of the omeprazole given via the oral route of administration. In the above-cited studies, as much as 48 mmoles of sodium bicarbonate in 300 ml of water must be ingested for a single dose of omeprazole to be orally administered.
The buffered omeprazole solutions of the above cited prior art require the ingestion of large amounts of sodium bicarbonate and large volumes of water by repeated administration. This has been considered necessary to prevent acid degradation of the omeprazole. In the above-cited studies, basically healthy volunteers, rather than sick patients, were given dilute buffered omeprazole utilizing pre-dosing and post-dosing with large volumes of sodium bicarbonate.
The administration of large amounts of sodium bicarbonate can produce at least six significant adverse effects, which can dramatically reduce the efficacy of the omeprazole in patients and reduce the overall health of the patients. First, the fluid volumes of these dosing protocols would not be suitable for sick or critically ill patients who must receive multiple doses of omeprazole. The large volumes would result in the distention of the stomach and increase the likelihood of complications in critically ill patients such as the aspiration of gastric contents.
Second, because bicarbonate is usually neutralized in the stomach or is absorbed, such that belching results, patients with gastroesophageal reflux may exacerbate or worsen their reflux disease as the belching can cause upward movement of stomach acid (Brunton, Agents for the Control of Gastric Acidity and Treatment of Peptic Ulcers, IN, Goodman AG, et al. The Pharmacologic Basis of Therapeutics. (New York, p. 907 (1990)).
Third, patients with conditions such as hypertension or heart failure are standardly advised to avoid the intake of excessive sodium as it can cause aggravation or exacerbation of their hypertensive conditions (Brunton, supra). The ingestion of large amounts of sodium bicarbonate is inconsistent with this advice.
Fourth, patients with numerous conditions that typically accompany critical illness should avoid the intake of excessive sodium bicarbonate as it can cause metabolic alkalosis that can result in a serious worsening of the patient""s condition.
Fifth, excessive antacid intake (such as sodium bicarbonate) can result in drug interactions that produce serious adverse effects. For example, by altering gastric and urinary pH, antacids can alter rates of drug dissolution and absorption, bioavailability, and renal elimination (Brunton, supra).
Sixth, because the buffered omeprazole solutions of the prior art require prolonged administration of sodium bicarbonate, it makes it difficult for patients to comply with the regimens of the prior art. For example, Pilbrant et al. disclose an oral omeprazole administration protocol calling for the administration to a subject who has been fasting for at least ten hours, a solution of 8 mmoles of sodium bicarbonate in 50 ml of water. Five minutes later, the subject ingests a suspension of 60 mg of omeprazole in 50 ml of water that also contains 8 mmoles of sodium bicarbonate. This is rinsed down with another 50 ml of 8 mmoles sodium bicarbonate solution. Ten minutes after the ingestion of the omeprazole dose, the subject ingests 50 ml of bicarbonate solution (8 mmoles). This is repeated at twenty minutes and thirty minutes post omeprazole dosing to yield a total of 48 mmoles of sodium bicarbonate and 300 ml of water in total that are ingested by the subject for a single omeprazole dose. Not only does this regimen require the ingestion of excessive amounts of bicarbonate and water, which is likely to be dangerous to some patients, it is unlikely that even healthy patients would comply with this regimen.
It is well documented that patients who are required to follow complex schedules for drug administration are non-compliant and, thus, the efficacy of the buffered omeprazole solutions of the prior art would be expected to be reduced due to non-compliance. Compliance has been found to be markedly reduced when patients are required to deviate from a schedule of one or two (usually morning and night) doses of a medication per day. The use of the prior art buffered omeprazole solutions which require administration protocols with numerous steps, different drugs (sodium bicarbonate+omeprazole+PEG 400 versus sodium bicarbonate alone), and specific time allotments between each stage of the total omeprazole regimen in order to achieve efficacious results is clearly in contrast with both current drug compliance theories and human nature.
The prior art (Pilbrant et al., 1985) teaches that the buffered omeprazole suspension can be stored at refrigerator temperatures for a week and deep frozen for a year while still maintaining 99% of its initial potency. It would be desirable to have an omeprazole or other proton pump inhibitor solution or suspension that could be stored at room temperature or in a refrigerator for periods of time which exceed those of the prior art while still maintaining 99% of the initial potency. Additionally, it would be advantageous to have a form of the omeprazole and bicarbonate which can be utilized to instantly make the omeprazole solution/suspension of the present invention which is supplied in a solid form which imparts the advantages of improved shelf-life at room temperature, lower cost to produce, less expensive shipping costs, and which is less expensive to store.
It would, therefore, be desirable to have a proton pump inhibitor formulation, which provides a cost-effective means for the treatment of the aforementioned conditions without the adverse effect profile of H2 receptor antagonists, antacids, and sucralfate. Further, it would be desirable to have a proton pump inhibitor formulation which is convenient to prepare and administer to patients unable to ingest solid dosage forms such as tablets or capsules, which is rapidly absorbed, and can be orally or enterally delivered as a liquid form or solid form. It is desirable that the liquid formulation not clog indwelling tubes, such as nasogastric tubes or other similar tubes, and which acts as an antacid immediately upon delivery.
It would further be advantageous to have a potentiator or enhancer of the pharmacological activity of the proton pump inhibitors. It has been theorized by applicant that the proton pump inhibitors can only exert their effects on H+, K+-ATPase when the parietal cells are active. Accordingly, applicant has identified, as discussed below, parietal cell activators that are administered to synergistically enhance the activity of the proton pump inhibitors.
Additionally, the intravenous dosage forms of proton pump inhibitors of the prior art are often administered in larger doses than the oral forms. For example, the typical adult IV dose of omeprazole is greater than 100 mg/day whereas the adult oral dose is 20 to 40 mg/day. Large IV doses are necessary to achieve the desired pharmacologic effect because, it is believed, many of the parietal cells are in a resting phase (mostly inactive) during an IV dose given to patients who are not taking oral substances by mouth (npo) and, therefore, there is little active (that which is inserted into the secretory canalicular membrane) H+, K+-ATPase to inhibit. Because of the clear disparity in the amount of drug necessary for IV versus oral doses, it would be very advantageous to have compositions and methods for IV administration where significantly less drug is required.
The foregoing advantages and objects are accomplished by the present invention. The present invention provides an oral solution/suspension comprising a proton pump inhibiting agent and at least one buffering agent. The proton pump inhibiting agent can be any substituted benzimidazole compound having H+, K+-ATPase inhibiting activity and being unstable to acid.
The inventive composition can alternatively be formulated as a powder, tablet, suspension tablet, chewable tablet, capsule, two-part tablet or capsule, effervescent powder, effervescent tablet, pellets and granules. Such dosage forms are advantageously devoid of any enteric coating or delayed or sustained-release delivery mechanisms, and comprise a proton pump inhibiting agent and at least one buffering agent to protect the proton pump inhibiting agent against acid degradation. Both the liquid and dry dosage forms can further include anti-foaming agents, parietal cell activators and flavoring agents.
In another embodiment, oral dosage forms are disclosed comprising a combination of enteric-coated or delayed-released proton pump inhibiting agent with an antacid(s). Such forms may optionally comprise a non-enteric-coated proton pump inhibiting agent.
Kits utilizing the inventive dry dosage forms are also disclosed herein to provide for the easy preparation of a liquid composition from the dry forms.
In accordance with the present invention, there is further provided a method of treating gastric acid disorders by orally administering to a patient a pharmaceutical composition(s) and/or dosage form(s) disclosed herein.
Additionally, the present invention relates to a method for enhancing the pharmacological activity of an intravenously administered proton pump inhibiting agent in which at least one parietal cell activator is orally administered to the patient before, during and/or after the intravenous administration of the proton pump inhibiting agent.
Finally, the present invention relates to a method for optimizing the type and amount of buffer desirable for individual proton pump inhibiting agents.